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Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2

Oliveira, Taiana M
Leitner, Alexander
Karuppasamy, Manikandan
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Published in Molecular cell. 2015, vol. 58, no. 6, p. 977-988
Abstract Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression.
Keywords Antifungal Agents/metabolism/pharmacologyBinding Sites/geneticsBiocatalysis/drug effectsBlottingWesternCarrier Proteins/chemistry/genetics/metabolismCell Cycle/drug effects/geneticsCell Cycle Proteins/chemistry/genetics/metabolismDrug Resistance/geneticsMass Spectrometry/methodsMechanistic Target of Rapamycin Complex 2MicroscopyElectronMultiprotein Complexes/chemistry/genetics/metabolismMutationPhosphatidylinositol 3-Kinases/chemistry/genetics/metabolismProtein StructureTertiarySaccharomyces cerevisiae/drug effects/genetics/metabolismSaccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/ultrastructureSirolimus/metabolism/pharmacologyTOR Serine-Threonine Kinases/chemistry/genetics/metabolism
PMID: 26028537
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Research group Groupe Loewith
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GAUBITZ, Christl et al. Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2. In: Molecular Cell, 2015, vol. 58, n° 6, p. 977-988. doi: 10.1016/j.molcel.2015.04.031 https://archive-ouverte.unige.ch/unige:103227

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Deposited on : 2018-03-27

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